Hemolytic disease of the fetus and newborn

Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by the destruction of fetal red blood cells (RBC) and subsequent anemia. It is commonly caused by a Rhesus (Rh) or ABO incompatibility between the mother and fetus, although other blood incompatibilities (e.g., Kell blood group incompatibility) and other conditions not caused by red cell alloimmunization (e.g., congenital heart defects) can also cause HDFN. In Rh incompatibility, maternal IgG antibodies form after maternal exposure to fetal Rh-positive blood during birth or pregnancy-related complications (e.g., fetomaternal hemorrhage). The initial pregnancy is not affected; however, subsequent pregnancies are at risk of fetal hemolysis and, in severe cases, intrauterine hydrops fetalis. ABO incompatibility, on the other hand, may lead to fetal hemolysis in the first pregnancy because of preexisting antibodies in the mother, and it usually has a milder course of disease. Newborns may present with pallor, jaundice, and hepatosplenomegaly. Diagnosis of HDFN involves clinical and laboratory assessment for evidence of antibody-mediated hemolysis (e.g., Coombs test). Prenatal imaging may be used to exclude hydrops fetalis. Treatment includes iron supplementation and, in the case of severe jaundice, phototherapy. In rare cases, extremely low hemoglobin (Hb) levels require transfusion of red cell concentrates. Since Rh incompatibility may be fatal, anti-D immunoglobulin prophylaxis is administered to Rh-negative pregnant women. ABO incompatibility, on the other hand, rarely presents with complications and does not require immunoglobulin prophylaxis.

HDFN is a condition characterized by blood group incompatibility between the mother and fetus that leads to the destruction of fetal erythrocytes by maternal antibodies.

• ABO incompatibility: present in ∼ 20% of all pregnancies; however, only 5–10% of newborns from these pregnancies are symptomatic.
• Rh incompatibility: rare following routine anti-D prophylaxis
• Kell blood group system incompatibility: second most common cause of severe HDFN after Rh disease
• Risk factors: maternal exposure to fetal blood during pregnancy ^[1]
  • Antenatal procedures (e.g., amniocentesis, cesarean delivery, termination of pregnancy)
  • Pregnancy-related complications (e.g., ectopic pregnancy, placental abruption)
  • Trauma

References:^[2][3]

ABO incompatibility

• Highest risk: mother with blood group O; newborn with blood group A or B
• Maternal antibodies (anti-A and/or anti-B) against nonself antigens of the ABO system are present even if sensitization has not occurred; , so fetal hemolysis may occur during the first pregnancy.

Rh incompatibility

• In an Rh-negative mother and Rh-positive newborn: maternal exposure to fetal blood (fetomaternal hemorrhage) → production of maternal IgM antibodies against the Rh antigen; → over time, seroconversion to Rh-IgG (able to cross the placenta)
• In a subsequent pregnancy with an Rh-positive newborn: rapid production of maternal IgG anti-D antibodies to fetal RhD antigens → Rh-IgG agglutination of fetal RBCs with hemolytic anemia → risk of HDFN with possible hydrops fetalis

Kell blood group system incompatibility ^[4][5]

• The Kell blood group system includes K (K1), k (K2), Kp^a, Kp^b, Js^a, and Js^bantigens (for more information, see “Kell antigen system”), which can trigger substantial immune responses.
• Responsible for up to 10% of severe cases of HDFN ^[6]
• Maternal exposure to Kell antigen in previous pregnancy through the placenta or through blood transfusions → sensitization and production of maternal anti-Kell antibodies → antibodies enter circulation of Kell-positive fetus through placenta → destruction of fetal RBC precursors and mature RBCs → ↓ production of RBCs and ↑ hemolysis → severe fetal anemia

Nonimmune hydrops fetalis ^[7]

• Definition: a subgroup of hemolytic diseases of the fetus and newborn not caused by red cell alloimmunization
• Epidemiology
  • Incidence: ∼ 1 in 4,000 pregnancies
  • Accounts for over 90% of all hydrops fetalis cases
• Etiology
  • Congenital heart defects and arrhythmias
  • Chromosomal aberrations (e.g., Turner syndrome, Down syndrome, trisomy 18)
  • Severe fetal anemia (e.g., thalassemia, twin-to-twin transfusion syndrome, fetomaternal hemorrhage)
  • Congenital TORCH infections (especially parvovirus B19 infection)
• Pathophysiology: severe fetal anemia → hypoxia →; ↓ hepatic and renal blood flow → activation of RAAS → ↑ central venous pressure and ↓ lymphatic flow → fetal edema ^[8]

Prenatal

• Hydrops fetalis (expected in cases of Rh incompatibility and in nonimmune hydrops fetalis)

Postnatal

• Neonatal anemia
• Hepatosplenomegaly
• Neonatal jaundice
  • Usually present at birth or manifests within the first 24 hours of life
  • In Rh incompatibility, unconjugated bilirubin levels may be dangerously high, causing kernicterus.
• Hypoxia
• Prematurity
• Scattered petechiae (rare but associated with poor prognosis) ^[9]

ABO incompatibility usually has a significantly milder course of disease than Rh incompatibility.

Anemia may conceal cyanosis.

The diagnosis of HDFN requires evidence of hemolysis in the presence of fetomaternal blood incompatibility.

Prenatal diagnosis

• Imaging
  • Ultrasound: to determine hydrops fetalis
    • Fetal pleural or pericardial effusions
    • Fetal ascites
    • Fetal subcutaneous or nuchal edema
    • Placental edema
  • Doppler sonography of fetal blood vessels: Increased flow rate indicates fetal anemia.

Postnatal diagnosis

• If the newborn has signs of hemolysis, conduct a Coombs test (either direct or indirect).
  • Rh incompatibility: positive
  • ABO incompatibility: weak positive or negative

ABO vs. Rh incompatibility

Differential diagnoses of petechiae in newborns

Neonatal alloimmune thrombocytopenia

• Description: a rare condition in newborns characterized by maternal-fetal platelet incompatibility resulting in fetal thrombocytopenia
• Epidemiology: the leading cause of severe thrombocytopenia in the newborn
• Pathophysiology: formation of maternal antibodies against fetal platelets (most commonly targeting platelet antigen 1a) → maternal IgG cross the placenta and result in the destruction of fetal platelets → fetal and neonatal thrombocytopenia
• Clinical features
  • Mild: asymptomatic thrombocytopenia
  • Moderate: petechia and/or ecchymoses within a few hours after birth
  • Severe: spontaneous intracranial hemorrhage

Other

• Immune thrombocytopenic purpura
• Kasabach-Meritt syndrome
• Perinatal infections
• For an overview of thrombocytopenias and disorders of platelet function, see “Differential diagnosis of platelet disorders.”

The differential diagnoses listed here are not exhaustive.

• Prenatal
  • Intrauterine blood transfusion via the umbilical vein, umbilical artery, peritoneal cavity, or heart (should only be performed in centers with experience in fetal transfusions.)
  • Possible IV immunoglobulin (IVIG) in severe cases
• Postnatal
  • Anemia: iron supplementation and, if necessary, RBC transfusion. ^[10]
  • Hyperbilirubinemia: phototherapy; if necessary, exchange transfusion with red blood cells
  • See “Treatment” in neonatal jaundice.
  • In severe cases, IV immunoglobulin (IVIG) may be administered.

References:^[10]

Screening

• ABO and Rh typing of the mother
  • Rh-positive mothers do not need further screening.
  • Rh-negative mothers: screening for anti-D antibodies
    • No anti-D antibodies (unsensitized mothers): antibody screening repeated at 28 weeks' gestation and at delivery. See “Anti-D immunoglobulin (RhoGAM)” below.
      
    • Anti-D antibodies manifest with an anti-D antibody titer > 1:8, which indicates maternal sensitization to fetal Rh antigens (sensitized mothers).; Further monitoring with amniocentesis and imaging is required for evidence of hemolysis.
• Fetomaternal hemorrhage in Rh-negative mother
  1. Conduct a rosette test (initial test of choice). This is a qualitative test that assesses whether fetomaternal hemorrhage has occurred.
     • The apt test is an alternative to the rosette test, but it only differentiates whether the origin of blood is fetal/newborn or from the mother, e.g., from:
       • Newborn gastrointestinal (stool, vomiting) or pulmonary bleeding
       • Antepartum hemorrhage (e.g., vasa previa)
  2. If the rosette test is positive, conduct a Kleihauer-Betke test.
     • Quantitative testing to evaluate fetomaternal hemorrhage ^[1]
     • The amount of fetal hemoglobin determines the amount of Anti-D immunoglobulin necessary.
     • Flow cytometry is an alternative, but its use is limited by equipment and costs.
• Fetal Rh genotyping

Anti-D immunoglobulin (RhoGAM)

• Background
  • Pathophysiology: See “Rhesus incompatibility” above.
  • Anti-D prophylaxis protects newborns in subsequent pregnancies.
  • Only indicated in unsensitized mothers
• Indication and implementation
  • Anti-D prophylaxis should be administered during the 28^th week of gestation; and within 72 hours following the birth of an Rh-positive baby.
  • The efficacy of anti-D prophylaxis relies on antibody-mediated immunosuppression.
• Further indications in Rh negativity
  • Following a miscarriage, ectopic pregnancy, or termination of pregnancy
  • Bleeding during pregnancy
  • Following invasive procedures (e.g., amniocentesis, chorionic villus sampling)
• Dosage
  • Standard dose: 300 mcg (1500 IU) IV/IM
  • If whole fetal blood is > 30 mL (i.e., fetal RBCs > 15 mL): 300 mcg (1500 IU) IM should be given for every 30 mL of fetal blood volume. ^[1][11]
  • Adjusted dose in the first trimester: 50–120 mcg ^[11]

References:^[2][12]